It's no big secret that alcohol makes most people feel pretty good, but scientists at UCSF and UC Berkeley have for the first time found evidence that liquor triggers the release of pleasure-inducing endorphins in the brain - and that heavy drinkers are especially influenced by those endorphins.

Studies of alcohol's effect on animal brains have shown for decades that endorphins - the body's tiny, natural proteins that behave like opiates - play a key role in the appeal of alcohol and why it can be addictive.

But the UC study is the first to demonstrate, using brain-imaging technology, what actually happens in human brains while a person is drunk, or at least tipsy. The findings, while not necessarily shocking, could help researchers develop more focused drug treatments for fighting alcoholism, said scientists involved with the study released Wednesday.

"Over the years, people have come up with a variety of hypotheses about how alcohol works in the brain. We know that it induces this endorphin release, and that's sort of unequivocal now," said Jennifer Mitchell, clinical project director of UCSF's Ernest Gallo Clinic and Research Center and lead author of the study.

"Heavy drinkers report a lot of pleasure from a drink of alcohol," she said. "That's why we think drug treatment could be effective - if we can block that high, eventually they'll learn that drink isn't worth it anymore."

Unpleasant drug

The current standard treatment for alcoholism is focused on self-help or psychotherapy - 12-step programs, for example, or inpatient facilities. Drugs exist, primarily naltrexone, to help people quit drinking, but those drugs aren't often prescribed, in part because many patients don't like taking them, Mitchell said.

Naltrexone works by blocking the receptors in the brain that link with endorphins - effectively cutting off the pleasure-inducing effects of endorphins - which might be why patients don't like the drug. But if scientists could refine the effects of naltrexone so that it blocks only the specific receptors associated with alcohol, the drug could be much more tolerable, Mitchell said.

"We believe this research will help us reverse-engineer the naltrexone to make it more specific," she said. "You don't want to block good feelings in general. You want it to be specific to the alcohol. That's the key."

The study was published in the journal Science Translational Medicine. Scientists studied the brains of 25 volunteers - 13 heavy drinkers and 12 light drinkers who acted as controls.

The researchers used a radioactive-tagged drug that behaves like endorphins to study what happens in participants' brains when they drink. Both the drug and the endorphins bind to the same receptor - called the mu opioid receptor. Every participant was injected with the drug and then scanned using positron emission tomography (PET scans), which enabled scientists to track the radioactive tag and identify which parts of the brain the injected drug was drawn to while the person was sober.

Alcohol's effects

The participants were then given a drink of a strong, lab-made alcohol, and injected with the same radioactive drug and scanned again. In the second scan, the injected drug was not found in two key sites - the orbitofrontal cortex and the nucleus accumbens - leading scientists to assume that endorphins flooded the mu receptors in those sites, forcing the injected drug out of the area.

All of the study participants had consumed enough to have a blood-alcohol level of about 0.05. After the second PET scan, the participants were interviewed about how intoxicated they felt.

Overall, there was no difference in the amount of endorphins released in the brains of heavy and light drinkers in the study. But in heavy drinkers, the amount of endorphins found in the orbitofrontal cortex was strongly tied to how much pleasure they reported from the one drink; in light drinkers, there was no such connection.

"There was a much stronger relationship between their subjective high and the endorphin release in the (heavy) drinkers," Mitchell said.

The areas of the brain affected by alcohol in the study are associated with reward and decision-making processes. The orbitofrontal cortex is also connected to the sense of taste, which may be one important, if fairly simple, reason for why alcoholics like to drink, said Dr. Howard Fields, director of human clinical research at the Gallo Center and an author of the study.

"Something is changing in the brains of the alcoholics that makes the alcohol taste better to them," he said. "At least, that's one possible interpretation of our data."

Both Fields and Mitchell pointed out that their study identified only one part of what is probably a very complex process happening in the brains of alcoholics. In fact, there may be different processes affecting different types of drinkers.

Just part of problem

"This was directly testing one idea," Fields said. "The problem is that alcohol acts at a lot of different targets in the brain, and there are probably 100 different theories about why it's addicting and makes you feel good."

This study will allow other researchers to narrow their focus on the role that endorphins play in alcohol addiction, said George Koob, a scientist with the Scripps Research Institute in La Jolla who studies neurobiology and alcoholism.

"Some people may be more vulnerable to having their endorphins tweaked. It could be that some people don't have very good endorphin release and alcohol is the only way for them to get that," Koob said. "These are the kinds of things that can be looked at now, based on this study. It could be really exciting."

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